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A BUFFET OF GLUCOSE:
Cancer cells use glycolysis to stimulate rapid cell growth // Researchers and pharmaceutical companies
are focusing on anti-metabolism treatments // But the root causes of cancer’s growth are still murky
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Cutting Cancer’s Power
BY CATHRYN DELUDE // ILLUSTRATIONS BY RICHARD WILKINSON
I
n this era of cancer genetics, we’ve come
to think of cancer as something like a car.
Runaway cell proliferation is driven by accelerators, or oncogenes, that are stuck
on go—in collusion with broken brakes,
or tumor suppressors, that can’t control a
tumor’s pedal-to-the-metal growth. A lengthening procession
of targeted therapies (Herceptin, Gleevec, Tarceva, Zelboraf)
attempt to block various accelerators, and they often succeed
in bringing a tumor to a screeching halt—until the malignancy
activates a different gas pedal and returns to the road.
Lately, increasing numbers of researchers have turned their
attention to the excessive amount of fuel that accelerating
cancers require, and to how tumors use the fuel. That focus on
the metabolism of cancer cells bridges the fields of oncology
and cellular metabolism, says Lewis Cantley, a biochemist and
the director of the Cancer Center at Beth Israel Deaconess
Medical Center, whose work has helped resurrect this longsidelined approach to fighting tumors. “If we can understand
the unique ways that cancer cells use energy, then we may be
able to exploit their weaknesses,” Cantley says.
Metabolism, in terms of the whole body, is a balancing act.
It’s part of a calories in, energy out equation, the reason that
eating too much and exercising too little leads to weight gain.
But metabolism also happens at a cellular level. Normal cells
take in sugar, or glucose, from the blood to generate heat and
to fulfill their appointed tasks. Cancer cells do the same thing,
but they burn through much more glucose—a supercharged
uptake that’s visible on FDG (fludeoxyglucose) PET scans. Oncologists commonly use this imaging technique to help locate
tumors, establish the stage of those cancers’ progression, and
determine whether they have stopped growing in response to
therapy or are relapsing or metastasizing.
Many researchers now believe, however, that taking advantage of cancer’s appetite for glucose could go beyond diagnosis and lead to effective treatments. It’s impossible to
deprive a patient’s cancer cells of glucose, because the liver
will synthesize additional sugar if the bloodstream has an insufficient supply. Yet it might be feasible to scramble the distinctive way that cancer cells metabolize glucose and starve
hungry cancer cells to death—or at least to use that approach
to complement other therapies.
D
eciphering cancer metabolism begins with adenosine
triphosphate, or ATP—the energy currency that all
cells use to power what they do. Under most conditions, cells use oxygen to burn glucose in their mitochondria,
located in cells’ cytoplasm, the gelatinous filling around the nucleus. For this, the cells use the tricarboxylic acid (TCA) cycle,
also known as the Krebs cycle and as oxidative phosphorylation. In the TCA cycle, glucose, oxygen and other chemicals
are modified, combined or broken down into components
(metabolites), some of which re-enter the cycle while others
go off to perform other duties. This process generates ATP,
with carbon dioxide as a by-product. Occasionally, though, a
cell will become oxygen-depleted, or anaerobic, such as when
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someone tries to sprint 500 yards. “For the last 100 yards, your
leg muscle cells aren’t getting oxygen,” says Raul Mostoslavsky,
a molecular biologist at Massachusetts General Hospital Cancer Center. Muscle cells are then forced to switch to glycolysis.
Compared with normal cellular metabolism, which can generate 36 units of ATP per molecule of glucose, glycolysis seems
grossly inefficient, producing just two units, with lactate as a
by-product. Lactate is acidic, and it’s what makes muscles ache
following anaerobic exercise, says Mostoslavsky.
But extreme exercise isn’t required to force cancer cells to
opt for glycolysis. In 1924, Otto Warburg, a German biochemist who later won the Nobel Prize, observed that malignant
cells use glycolysis even when they have enough oxygen. Aerobic glycolysis, now known to happen in almost all cancers, is
called the Warburg effect.
Why would cancer cells switch from a mechanism that produces maximum energy to such a wasteful use of glucose? Warburg proposed that it resulted from damaged mitochondria,
leaving the cell no other choice. He also contended that this
altered metabolism was the cause of cancer, and for decades
that notion was at the center of cancer research.
Cantley, as a graduate student in biochemistry during
the 1970s, was part of that wave. But researchers eventually
learned that the mitochondria in most cancer cells are not in
fact damaged, and that most cancer cells freely select glycolysis. And once James Watson and Francis Crick had defined
the structure of DNA, genetic research blossomed. The first
cancer-causing oncogenes were discovered, and the focus of
efforts to understand and control cancer shifted to its genetic
underpinnings. Cancer metabolism, it seemed then, was a mere
side effect of what happened in genes.
That view persisted until recently, when the conventional
wisdom began to reverse itself again. “It took about 20 years to
figure out what oncogenes do—and guess what?” says Cantley.
“They reprogram the metabolism, and that promotes cancer. If
we turn off one oncogene with a targeted therapy, another one
turns on to rewire some other metabolic pathway. So why not
just target metabolism?”
U
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ntil about five years ago, though, science couldn’t explain
why cancer cells with sufficient oxygen would consistently opt for glycolysis—which, after all, produces just
a fraction of the energy that normal metabolism can generate.
Then Craig Thompson, a medical oncologist and president and
CEO of Memorial Sloan-Kettering Cancer Center in New York
City (along with Cantley and one of his postdoctoral students,
Matthew Vander Heiden) rethought the problem. What if there
was something else the cells needed even more than energy? At
the time, Thompson was director of the Abramson Cancer Center at the University of Pennsylvania, and as a medical oncologist
with training in immunology, he was studying normal, healthy
white blood cells, or lymphocytes, to understand how fastdividing cells make the decision to divide. Rapidly proliferating
lymphocytes also choose glycolysis, and he realized that it was
because glycolysis gives those cells more of what they need to
replicate themselves: the building blocks of new cells.
When cells are growing fast or dividing, they have to create new proteins for receptors, new lipids for membranes,
new nucleotides for DNA and new fatty acids for cholesterol.
In glycolysis, more of the components of glucose are available
to form the bricks and mortar of growing and dividing cells.
Thanks to that insight, subsequently confirmed in numerous
labs, “the whole field exploded,” says Mostoslavsky.
This new view of cancer metabolism also conjures up a new
metaphor: a cabin in the woods. Trees (glucose) can be burned
as fuel for heat, or they can be used to build a cabin. A normal
cell is like a cabin that is content to burn a few logs at a time
for warmth. A cancer cell is a cabin that wants to expand (cell
growth) and then build a cluster of additional cabins to create
a tumor (cell division). In biochemistry, the heat-generating
metabolism, called catabolism, happens in the mitochondria,
in the TCA cycle. The building-block-producing metabolism,
or anabolism, uses glycolysis. “Warburg thought glycolysis was
wasteful,” says Thompson. “It’s not. It allows the cell to deal
with its metabolic problem of how to grow and multiply.”
In most adult tissues, cells go about their daily business—
absent a command from a growth factor, such as epidermal
growth factor (EGF), they don’t really need to grow, much less
divide. And even when a growth factor sends its signal to grow
by attaching to receptors on the cell surface, a cell must decide
whether it has sufficient nutrients to obey.
That work is carried out through a molecular pathway known
as PI3K—phosphoinositide 3 kinase—an enzyme Cantley discovered during the 1980s that relays signals and activates other
enzymes or genes. The PI3K signaling pathway is normally
tightly controlled, but in many cancers that control is absent.
Any of several mutations and aberrations can push the pathway
into a hyperactivated state, pressing a cell to grow and divide
more than its environment calls for. The pathway increases the
activation of HIF-1a (hypoxia inducible factor 1 alpha) and produces more glucose transporters on the cell surface—both key
changes that promote glycolysis in cancer cells.
Insulin, the hormone that normally tells muscle and
fat cells to take in glucose, also activates PI3K, Cantley
discovered. Those cells then use the glucose for anabolic growth. It turns out that lots of epithelial
tumors (carcinomas) have insulin receptors too.
“The cancer cells are getting what muscle and
fat cells usually get,” he says, “and that changes
how they function”—in ways that fulfill cancer’s
need for new building blocks.
R
esearchers now know that a cancer cell derives benefits from glycolysis that go beyond having plenty of
raw materials for new cells. For one thing, glycolysis
can still produce a lot of energy. Though the TCA cycle generates many more units of ATP per molecule of glucose, glycolysis happens so quickly that it actually generates more ATP per
second than the normal process does. Moreover, cell metabolism is not an either-or proposition. Cancer cells using glycolysis also continue to metabolize glucose in their mitochondria
using the TCA cycle, to produce still more energy. That, in
turn, generates free radicals—unstable molecules that can
damage DNA, creating additional mutations that allow the
Off the Shelf //
A drug approved for type 2 diabetes may also target cancer’s
wayward metabolism.
As researchers continue to probe the role of cell metabolism in
cancer—and to develop new therapies designed to starve cancer cells
of nourishment—they’ve found that one existing treatment already
targets metabolism.
Some scientists believe that metformin, the drug most commonly
prescribed for type 2 diabetes, targets cancer metabolism. Metformin
reduces glucose production in the liver, in turn lowering blood sugar
levels that are elevated in diabetes. Insulin, an alternative diabetes
treatment, cuts blood sugar by encouraging cells to absorb glucose.
Studies have shown that diabetes patients taking metformin have
lower rates of cancers than those who take insulin, and Lewis Cantley,
director of the Cancer Center at Beth Israel Deaconess Medical
Center, is one of those who believe metformin actively protects against
cancer—because reducing blood sugar also lowers the level of insulin
in the blood. Insulin, by helping cancer cells suck in glucose, aids in
the growth of some tumors.
Researchers also suggest that insulin itself is behind the higher
cancer risk of diabetic patients who opt to take insulin rather than
metformin. Several current studies will try to settle this question.
tumor to become more invasive, infiltrating tissues and migrating to other parts
of the body. Glycolysis’ waste product,
lactic acid, might also make surrounding tissue more vulnerable
to a tumor’s infiltration.
Moreover, cancer’s metabolic
reprogramming goes beyond
glycolysis and the Warburg
effect. Malignant cells also
depend on another fuel, glutamine, an amino acid that cells can
metabolize to produce both energy
and building blocks. Glutamine, unlike
glucose, contains nitrogen, a key component of the nucleotides in DNA, RNA and ribosomes, which make up much
of the mass of a cell—and that all have to be duplicated when
cells divide. It turns out that the oncogene Myc, essential for
glycolysis, also directs cancer cells to scavenge glutamine out
of the bloodstream. By inducing both glycolysis and glutamine
metabolism, Myc uniquely supports the synthesis of the rapidly proliferating cells.
Not all cancers show up on FDG PET scans, and that could
be because some use glutamine metabolism rather than glycolysis. Or they could depend on still another nutrient, the
amino acid glycine. A May 2012 article in Science found that,
in a study of 1,300 samples of tumors from early-stage breast
cancer patients, those whose tumors had higher levels of
glycine synthesis were more likely to die from the disease.
Researchers know very little about how the body regulates
glycine metabolism. Yet its contribution to tumor cell proliferation only increases the evidence that changes in metabolism are
a cause of cancer and not just a consequence, according to Leif
Ellisen, a cancer genetics researcher and oncologist who directs
the MGH Translational Research Laboratory. “Knowing that
these metabolic changes actually drive cancer growth gives us an
important rationale to target their pathways as therapy,” he says.
That case became even stronger with the discovery in 2008
of a mutated gene for a metabolic enzyme called IDH (isocitrate dehydrogenase) in some leukemias, brain cancers, and gall
bladder and gastrointestinal cancers. The mutation allows cells
to synthesize an “oncometabolite” called 2-hydroxyglutarate
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(2HG), which modifies other enzymes, promotes the production of lipids and enhances tumor growth. IDH is mutated early
in the development of those cancers, supporting the theory
that cancer cells evolve toward altered metabolism, “selecting” mutated genes as they develop. Now researchers are finding additional mutated metabolic enzymes that can behave as
oncogenes, says Chi Dang, a medical oncologist and cancer
biologist who directs the Abramson Cancer Center, and such
discoveries are helping convince skeptics that alterations in
metabolism are not mere “epiphenomena” or side effects.
T
hese discoveries support the notion that by rewiring
their metabolism, cancer cells become “addicted” to
nutrients—a weakness ripe to be exploited. When normal cells sense a shortage of nutrients, they can slow down to
conserve their energy. But a cancer cell’s imperative is to grow
and divide, and if it doesn’t get sufficient nutrients, it may go
into autophagy—consuming itself in an attempt to produce the
building blocks for new cells. Autophagy eventually kills cells,
so new therapies that deprive cells of nutrients or otherwise
thwart metabolism will likely cause more harm to cancer cells
than to normal cells. In 2007, Lewis Cantley, Craig Thompson
and Tak Wah Mak, a researcher at the University of Toronto,
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founded Agios, a Boston biotechnology company, to develop
anti-metabolism agents, and many other biotech firms and
pharmaceutical companies are exploring similar strategies.
Much of the effort to impede cancer metabolism focuses
on the PI3K pathway that is hyperactivated in so many cancers. PI3K inhibitors are the subject of some 100 clinical trials, including one that will test whether a cancer treatment’s
early failure to reduce glucose uptake, as measured by FDG
PET, can predict whether the therapy will fail to shrink a patient’s tumor. Most researchers expect that combining such
agents (and other anti-metabolism drugs) with targeted therapies or chemotherapy will work better than any single drug
can do on its own.
Researchers also find the pyruvate kinase (PK) enzyme intriguing. PK is a gatekeeper that helps determine whether a cell
metabolizes glucose using the TCA cycle or diverts it to other
pathways for anabolic growth. PK comes in several forms, and
many normal adult cells use PKM1, which favors the TCA cycle.
When cells become cancerous they use PKM2 in glycolysis instead, and Myc and HIF-1a, the oncogenes that affect metabolism, may influence that switch. “Because PKM2 is a common
denominator in all cancers and clearly distinguishes them from
many normal cells, it is a potential drug target,” says Matthew
These discoveries support the notion that by rewiring
their metabolism, cancer cells become “addicted” to
nutrients—a weakness ripe to be exploited.
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Vander Heiden, now a cancer researcher at the MIT Koch Institute for Integrative Cancer Research who studies this enzyme.
Another possibility is to target glutamine metabolism. According to John Blenis, a cell biologist and biochemist at Harvard Medical School, many cancer cells in the lab have difficulty
surviving without glutamine, whereas normal cells in culture can
cope with low glutamine by shutting down growth and energy
use. As with glucose, the body makes more glutamine if there’s a
shortfall, so it’s impossible to deplete directly. However, in 2010,
Blenis, with Vander Heiden, Cantley and colleagues, found that
interfering with how cells metabolize glutamine can limit tumor
cell growth and survival.
Yet cancer metabolism, like everything else that happens in
tumors, is very complex, and a therapy that’s effective against
one metabolic process may not work against another. Still,
laying siege to cancer cells’ supply lines may cast a wider net
than targeted therapies aimed at rare oncogenic mutations.
Indeed, one widely used cancer treatment—methotrexate—
works by interfering with the metabolism of folate, an anabolic brick used to build new DNA. And drugs that treat other
diseases by affecting metabolic pathways might also turn out
to inhibit cancer.
S
o where does altered metabolism rank as a cause of cancer? “There’s quite a debate about this in the community
now,” says Daniel Haber, director of the MGH Cancer
Center. He notes that the altered metabolite produced by the
IDH mutation appears to indirectly affect how genes are regulated. It does so by inhibiting other enzymes that modify chromatin, the protein packaging around spools of DNA, by opening
or closing a spool to raise or lower the activity level of a gene in
that area. Thus, Haber muses, altered cancer metabolism is not
just about energy supply, but also directly affects gene expression through regulating chromatin, and that “closes the loop’”
between metabolism and genetics—but still poses the chickenor-the-egg problem of which came first.
One way of thinking about that problem, Ellisen suggests,
is that “a cell needs successive mutations, or hits, to become
a cancer cell.” Some of those hits affect tyrosine kinases,
enzymes that promote cancer by stimulating abnormal cell
growth and proliferation. “But those activities require energy
and building blocks,” he says. “So a cell that rewires its metabolism early on to scarf up nutrients from the environment
is more likely to do what the tyrosine kinase pathway sets in
motion; it’s more likely to have all the things it needs to become a tumor.”
And some metabolic mutations, which themselves can promote cancer-causing changes in the cell, will be more successful if they’re followed by mutations in tyrosine kinases or transcription factors that stimulate cell growth. “Maybe the normal
versions of oncogenes and tumor suppressors originally evolved
to regulate metabolism, and their mutations alter metabolism
in ways that inevitably become oncogenic,” says Thompson.
“It took us 80 years to bring the revealing observations of
Otto Warburg back from obscurity,” says Mostoslavsky at
MGH. “Now that we widely acknowledge cancer metabolism
as a main player in cancer, it will take much less time to exploit
metabolism in tackling this devastating disease.”
DOSSIER
1. “Links Between Metabolism and Cancer,” by Chi V. Dang, Genes &
Development, May 1, 2012. Dang reviews the evolution of the theory
that altered cellular metabolism contributes to cancer, in light of the
discovery of oncogenes and oncometabolites.
2. “The Metabolic Profile of Tumors Depends on Both the Responsible
Genetic Lesion and Tissue Type,” by Mariia O. Yuneva et al., Cell
Metabolism, Feb. 8, 2012. An account of the discovery that tumors
in mice metabolize glucose and glutamine differently depending on
whether they are induced by the Myc or Met oncogene and on which
tissue the tumors arise in.
3. “Targeting Cancer Metabolism: a Therapeutic Window Opens,” by
Matthew G. Vander Heiden, Nature Reviews Drug Discovery, Aug.
31, 2011. Can we therapeutically target the metabolic alterations in
cancer cells? We already have, since some approved drugs intervene
in cancer cells’ specific metabolic needs, but research into how altered
metabolism promotes cancer is leading to more directed efforts.
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